This document is updated periodically as new research findings in IPF are published.

What Causes IPF? (Etiology/Pathogenesis of IPF)

Since it's still called "idiopathic," you probably figured out already that the cause(s) of IPF remain unknown. Researchers use a paradigm for studying idiopathic pulmonary fibrosis called "aberrant repair." After an injury to the alveolar epithelium, fibroblasts appear in the interstitium (how is not known), and produce collagen (scar tissue) in so-called fibroblastic foci. Airway smooth muscle cells are also present in abnormal numbers in the interstitium, stimulating some mild inflammation whose contribution to IPF pathogenesis is unclear. As the process evolves, the radiographic and histologic patterns of usual interstitial pneumonia--required for the diagnosis of idiopathic pulmonary fibrosis--become apparent on imaging and biopsy. The fibrotic, scarred interstitium impairs gas exchange (reducing DLCO and eventually causing hypoxemia) and elastic recoil of the lung (causing a restrictive pattern on pulmonary function testing).

Pirfenidone for IPF (CAPACITY Trials)

In 2011, Noble et al reported the results of the CAPACITY trials, which were two Phase III placebo-controlled trials in North America and Europe enrolling 779 patients. Pirfenidone reduced FVC decline by ~4% at 72 weeks in one trial; in the other, it did not. Combining and analyzing the data together, pirfenidone reduced FVC decline by 2.5% compared to placebo. Adverse effects were mild overall but included common gastrointestinal symptoms, rash, and photosensitivity. Authors concluded in The Lancet that pirfenidone is “an appropriate treatment option” for idiopathic pulmonary fibrosis, but the FDA felt otherwise, and asked InterMune (makers of pirfenidone) to perform another randomized trial (ASCEND-3, see below) before FDA would consider approval. Lancet 2011;377:1760-1769.

Pirfenidone is approved for use in Japan, largely based on an earlier trial in ERJ of 275 patients in which pirfenidone reduced FVC decline by 70 mL compared to placebo and improved a soft endpoint of "progression-free survival."

PANTHER-IPF Stopped Early: Prednisone + Azathioprine Harmful in IPF

The PANTHER-IPF trial started out with three arms, each including about 80 patients with idiopathic pulmonary fibrosis: one placebo, another N-acetylcysteine (NAC) only, and a third with NAC, prednisone and azathioprine (Imuran). In October 2011, it became clear that prednisone and azathioprine were harmful--with many more deaths, hospitalizations, and adverse events--and that arm was stopped for safety. The N-acetylcysteine and placebo arms continue on. Prescribing prednisone and azathioprine for IPF now seems like a very bad idea. Read more about PANTHER-IPF here.

Treatments for Idiopathic Pulmonary Fibrosis; Clinical Trials in IPF

There's still no proven effective treatmentfor IPF, except for lung transplant. Trials of interferon-gamma, bosentan, imatinib mesilate, and etanercept have all been negative, although authors point out that trials have only included people with mild-to-moderate disease. Authors felt the CAPACITY trials suggested clinical benefit of pirfenidone, although the FDA disagreed.

Multiple phase 2 and phase 3 randomized clinical trials in IPF are ongoing at this writing:

ACE-IPF, warfarin vs. placebo in 256 people with advanced disease (NIH-funded) was recently stopped early, due to a lack of likely benefit from warfarin.

ASCEND-3, InterMune's follow-up to CAPACITY 1 and 2 that was demanded by the FDA before they would reconsider approval of pirfenidone, is in process.

Lung transplant is the only therapy known to prolong survival in IPF, but the 5 year survival after transplant is only 44%. Stem-cell therapies and bioengineering are years away from clinical practice, but are encouraging in experimental models.

Sildenafil improves gas exchange in patients with severe pulmonary fibrosis and pulmonary hypertension, and can improve quality of life and dyspnea in advanced IPF in some patients, authors in the Lancet review report.

Treating gastroesophageal reflux disease (GERD), which may have a role in pathogenesis or disease acceleration due to microaspiration, is justified, but an "aggressive" approach (Nissen fundoplication) needs further study before wholesale recommendation. Read more about GERD and IPF here.

Pulmonary rehabilitation is appropriate for people with idiopathic pulmonary fibrosis who are motivated. Limited evidence suggests pulmonary rehab is beneficial for patients with IPF, although the trial was small and the improvements from exercise were also small and short-lived.

New Prognosis & Staging Model for IPF: the "GAP Index"

In May 2012, Brett Ley et al published in Annals of Internal Medicine a novel, validated model for prognosis and staging of idiopathic pulmonary fibrosis (IPF), which they called the GAP index for its use of Gender, Age and Physiology as key predictive variables. The GAP index predicted survival with IPF as well or better as any measure or scheme proposed thus far, albeit only in broad categories of risk. We reviewed the GAP model here.